1. Field of the Invention
The present invention relates to derivatives of swainsonine, which are useful as anticancer agents and as glycosidase inhibitors. The present invention also relates to methods of preparing such derivatives and intermediates useful for preparing said derivatives.
2. Discussion of the Background
The indolizidine alkaloid (-)-swainsonine is of long standing interest due to its diverse biological activity. For the isolation from the fungus Rhizoctonia leguminicola, see:
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For the isolation from the legume Swainsona canescens, see:
For the isolation from the locoweed Astragalus lentiginosus, see:
For the isolation from Weir vine, see:
For a review of the synthesis and biological activity of swainsonine and other glycosidase inhibitors, see:
Nishimura. Y. In Studies in Natural Products Chemistry; Atta-ur-Rahmaii, Ed.; Elsevier: Amsterdam, vol. 10; pp. 495-583 (1992).
(-)-Swainsonine may be considered an azasugar analog of mannose, and is indeed a potent inhibitor of many mannosidases including the glycoprotein processing enzyme mannosidase II (see: Elbein, A. D., Ann. Rev. Biochem., vol. 56, pp. 497-534 (1987); Cenci Di Bello, I. et al, Biochem. J., vol. 259. pp. 855-861 (1989); Winchester, B. et al; Glycbiology, vol. 2, pp. 199-210 (1992); and Kaushal G. P. et al, Methods in Enzymology, vol. 230, pp. 316-329 (1994)). Swainsonine is the first glycoprotein-processing inhibitor to be selected for clinical testing as an anticancer drug (see: Goss, P. E. et al Clin. Cancer Res., vol. 1, pp. 935-944 (1995); and Das, P. C. et al, Oncol. Res., vol. 7, pp. 425-433 (1995)).
A great deal of effort has been expended on developing synthetic routes to swainsonine. See e.g.,
For a synthesis of the non-natural (+)-enantiomer of swainsonine, see:
For formal syntheses, see:
However, there is still a need for other compounds which exhibit similar anticancer and glycosidase inhibition properties as swainsonine.
Thus, there remains a need for compounds which exhibit anticancer activity. There also remains a need for compounds which inhibit glycosidase enzymes. There also remains a need for intermediates and methods useful for preparing such compounds.